Ghrelin is a hormone which has been shown to be the endogenous ligand for a G protein-coupled receptor (GPCR), type 1 growth hormone secretagogue receptor (hGHS-R1a) (Howard et al., Science, 1996, 273, 974-977).
Ghrelin is primarily synthesized in the stomach (Kojima et al., Horm. Res., 2001, 56 (Suppl. 1), 93-97. It has been found that levels of ghrelin are elevated in response to fasting or extended food restriction (Nakazato et al., Nature, 2001, 409, 194-198). A large number of effects of ghrelin in humans have been reported (see for example US patent application US2008/0194672, background section).
Ghrelin has been observed to improve gastrointestinal (GI) motility (Murray et al., Gastroenterology, 2003, 125, 1492-1502) and symptoms associated with conditions of altered GI transit like gastroparesis (e.g. Tack et al., Aliment Pharmacol Ther, 2005, 22: 847-853) and functional dyspepsia (e.g. Akamizu et al., Eur J. Endocrinol. 2008, 158, 491-498). Thus, ghrelin agonists may be useful in treating conditions associated with reduced or restricted GI motility.
Ghrelin has been observed to have additional endocrine effects including modulation of growth hormone (GH) levels (Howard et al., Science, 1996, 273, 974-977; Kojima et al., Nature 1999, 402, 656-660) as well as control of appetite, satiety and energy homeostasis (Cummings, Physiol Behav, 2006, 89, 71-84). Ghrelin receptor agonists may therefore be useful as therapeutics for conditions where modulation of GH release and/or food intake could be beneficial, for example for conditions such as growth retardation, muscle wasting disorders (e.g. sarcopenia or cachexia associated with, for example, cancer, chronic obstructive pulmonary disease (COPD), congestive heart failure (CHF), renal failure or Parkinson's Disease), anorexia and recovery from acute trauma (e.g. burns, spinal cord injury, hip fracture, head trauma and major surgery) or critical illness (DeBoer, 2011, Mol Cell Endocrinol).
Hence, it is the object of this invention to provide novel ghrelin receptor agonists.
WO 97/11697 (Merck) describes 3-spirolactam, 3-spiroamino, 3-spirolactone and 3-spirobenzopyran piperidines and pyrrolidines for the release of growth hormone.